Substituted piperazines

Abstract

Compounds are provided that act as potent antagonists of the CCR1 receptor, and which have been further confirmed in animal testing for inflammation, one of the hallmark disease states for CCR1. The compounds are generally aryl piperazine derivatives and are useful in pharmaceutical compositions, methods for the treatment of CCR1-mediated diseases, and as controls in assays for the identification of competitive CCR1 antagonists.

Description

CROSS-REFERENCES TO RELATED APPLICATIONS[0001]This application claims the benefit of Provisional Application Ser. No. 60 / 453,711, filed Jun. 12, 2002, (originally U.S. Ser. No. 10 / 171,398, filed Jun. 12, 2002) the contents of which is incorporated herein by reference.REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAM LISTING APPENDIX SUBMITTED ON A COMPACT DISK.[0002]NOT APPLICABLESTATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0003]This application was supported in part by DARPA Grant No. N65236-99-1-5420. The government of the United States may have certain rights in this application.BACKGROUND OF THE INVENTION[0004]The present invention provides compounds, pharmaceutical compositions containing one or more of those compounds or their pharmaceutically acceptable salts, which are effective in inhibiting the binding of various chemokines, such as MIP-1α, leukotactin, MPIF-1 and RANTES, to the CCR1 receptor. As antagonists or...

AI Technical Summary

Benefits of technology

[0013]The symbol L1 represents a linking group having from one to three main chain atoms selected from the group consisting of C, N, O and S and being optionally substituted with from one to three substituents selected from the group consisting of halogen, phenyl, —ORi, —OC(O)Ri, —NRiRj, —SRi, —Rk, —CN, —NO2, —CO2Ri, —CONRiRj, —C(O)Ri, —OC(O)NRiRj, —NRjC(O)Ri, —NRjC(O)2Rk, —X4ORi, —X4OC(O)Ri, —X4NRiRj, —X4SRi, —X4CN, —X4NO2, —X4CO2Ri, —X4CONRiRj, —X4C(O)Ri, —X4OC(O)NRiRj, —X4NRjC(O)Ri and —X4NRjC(O)2Rk, wherein X4 is selected from the group consisting of C1-4 alkylene, C2-4 alkenylene and C2-4 alkynylene and each Ri and Rj is independently selected from hydrogen, C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, heteroaryl, aryl-C1-4 alkyl, and aryloxy-C1-4 alkyl, and each Rk is independently selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, heteroaryl, aryl-C1-4 alkyl, and aryloxy-C1-4 alkyl. In certain preferred embodiments, the linking groups are unsubstituted, while in other preferred embodiments, substituents are present that can increase partitioning into selected solvents or into selected tissues. For example, addition of a hydroxy group to a propylene linkage will generally provide compounds having more favorable solubility in water. Preferably, L1 is selected from —CH2—, —CH2CH2—, —CH2CH2CH2—, —CH2O—, —CH2NH—, —CH2OCH2— and —CH2NHCH2—.

[0014]In addition to the compounds provided herein, the present invention further provides pharmaceutical compositions containing one or more of these compounds, as well as methods for the use of these compounds in therapeutic methods, primarily to treat diseases associated with CCR1 signalling activity.

Problems solved by technology

While function-blocking antibody and small peptide therapies are promising, they suffer from the perils of degradation, extremely short half-lives once administered, and prohibitive expense to develop and manufacture, characteristic of most proteins.

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